Is COL4A1 p.Pro552= (c.1656C>T) pathogenic?

COL4A1 p.Pro552= (c.1656C>T) is classified Likely benign in COL4A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-28). Ultra-rare (popmax 0.0231%, sas); Associated with autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome.

What condition is associated with COL4A1 p.Pro552= (c.1656C>T)?

COL4A1 p.Pro552= (c.1656C>T) is associated with autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome, brain small vessel disease 1 with or without ocular anomalies, retinal arterial tortuosity (ClinVar).

How common is COL4A1 p.Pro552= (c.1656C>T) in the general population?

COL4A1 p.Pro552= (c.1656C>T) is ultra-rare (popmax 0.0231%, sas) (gnomAD).

How is HANAC syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

COL4A1 p.Pro552=

c.1656C>T · rs576690537 · VCV1572036

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, sas)

Conditions

autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.9	GERP -3.5
Overall
CADD	5.363	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0231% South Asian · 21/91,068 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.0018% 29/1,613,926 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0231%	4,337
Middle Eastern	0.0166%	6,032
Remaining individualsnot grpmax-eligible	0.0032%	31,247
European (non-Finnish)	0.000424%	235,978

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: COL4A1
Protein: p.Pro552=
Coding: c.1656C>T
MANE Select: NM_001845
dbSNP: rs576690537
Type: single nucleotide variant
Location: chr13:110187210 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.43 · 4 PDB
Residue 552: the 'triple-helical region' region; the 'disordered' region

Full COL4A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: brain small vessel disease 1 with or without ocular anomalies retinal arterial tortuosity microangiopathy and leukoencephalopathy, pontine, autosomal dominant hemorrhage, intracerebral, susceptibility to

For HANAC syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

COL4A1 p.Pro552Leu Uncertain significance ★ ⚠ same residue
COL4A1 p.Pro552Ser Uncertain significance ★ ⚠ same residue
COL4A1 c.1991-2A>G Likely pathogenic ★★ same condition
COL4A1 c.2458+1G>A Pathogenic ★★ same condition
COL4A1 c.2458+2T>C Pathogenic/Likely pathogenic ★★ same condition
COL4A1 c.3742+1G>A Pathogenic ★★ same condition
COL4A1 c.388-1G>C Pathogenic/Likely pathogenic ★★ same condition
COL4A1 c.4250-1G>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/col4a1-p-pro552 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown